Several approaches have been taken for prolonged delivery of a drug at a controlled rate. For example, the NORPLANT® (The Population Council New York, N.Y.) device uses implantable diffusional systems. The NORPLANT® device required the placement of 6 levonorgestrel-filled silastic capsules under the skin (Darney, Current Opinion in Obstetrics and Gynecology 3:470-476 (1991)). Protection from conception for up to five years was achieved. The implants operated by simple diffusion, that is, the drug diffused through a polymeric material at a rate that was controlled by the characteristics of the drug formulation and the polymeric material. Darney describes other biodegradable implants, e.g., the CAPRANOR™ (University of California, San Francisco, Calif.) system and norethindrone pellets. These systems were designed to deliver contraceptives for about one year and then dissolve. The CAPRANOR™ system used poly(ε-caprolactone) capsules filled with levonorgestrel. Norethindrone pellets typically consisted of 10% pure cholesterol with 90% norethindrone.
Implantable infusion pumps have also been described for delivering drugs by intravenous, intraarterial, intrathecal, intraperitoneal, and epidural pathways. Such pumps are typically surgically inserted subcutaneously into a pocket of tissue in the lower abdomen provide for controlled delivery of an drug. A number of systems for insulin delivery, pain management, and chemotherapy delivery have been described (e.g., Health Services/Technology Assessment Text (HSTAT), External and Implantable Infusion Pumps, by Ann A. Graham, C.R.N.A., M.P.H., Thomas V. Holohan, M.D., Health Technology Review, No. 7, Agency for Health Care Policy and Research Office of Health Technology Assessment, January 1994).
Another approach for prolonged delivery of a drug uses osmotic delivery devices. Such a device can be implanted into a subject to release a drug in a controlled manner for a predetermined administration period. In general, these devices operate by imbibing fluid from the outside environment and releasing amounts of the drug corresponding to the imbibed fluid. An example of one such osmotic delivery device is the VIADUR® (Bayer HealthCare Pharmaceuticals, Wayne, N.J.) device. The VIADUR® device is a titanium implant drug-delivery system using DUROS® (ALZA Corporation, Mountain View, Calif.) technology to manage the symptoms associated with advanced (stage 4) prostate cancer by delivering leuprolide acetate. Treatment using the VIADUR® device reduces the amount of testosterone produced and circulated in a subject's body and provides a continuous therapy for 12 months.
The above-described devices and formulations have been useful for delivering drugs to a fluid environment of use. Although these devices have found application for human and veterinary purposes, there remains a need for devices, formulations, and methods of administration that are capable of delivering multiple drugs reliably to a subject at a controlled rate over a prolonged period of time.